Adipokines (e.g. leptin, TNFalpha, resistin and adiponectin) are fat-derived hormones with profound metabolic functions clinically relevant to our understanding of obesity, diabetes and atherosclerosis. Adiponectin has been tightly linked to decreased insulin sensitivity and is therefore of great clinical significance to the treatment of type II diabetes. To date, the vast majority of research has focused on the peripheral actions of adiponectin where it profoundly influences glucose utilization and fatty acid oxidation. Recently two adiponectin receptors (AdipoR1 and AdipoR2) were isolated with differing affinity for adiponectin (Yamauchi et al. Nature 2003). AdipoR1 is expressed not only in peripheral tissues (e.g. muscle, liver), but also in brain. A similar but non-identical expression pattern including brain was reported for AdipoR2. To our knowledge, these are the first definitive data that demonstrate adiponectin receptor expression in brain tissues, suggesting that adiponectin, acting through these receptors, can influence brain functions. However, the specific sites of adiponectin receptor RNA expression within the brain were not determined. This information would substantially influence our thinking of the brain systems sensitive to this metabolically important hormone. In this proposal, we present intriguing preliminary data on the distribution of adiponectin receptor RNAs in the rat CNS. These in situ hybridization (ISH) data strongly suggest that adiponectin receptors and hence, adiponectin may have roles in the regulation of plasma osmolarity, water/electrolyte balance and possibly other neuroendocrine functions. In Specific Aim 1, we plan to carefully evaluate the neuroanatomical sites of expression of adiponectin receptors to identify the precise relationship(s) between adiponectin receptors and specific neuroendocrine neuropeptide circuits using ISH methods. In Specific Aim 2, we plan to generate a novel mouse model that will permit us to determine the physiological significance of brain adiponectin receptor 1 expression. To accomplish this goal, we will knock out the adiponectin receptor 1 gene in the mouse brain using brain region specific cre recombination strategies. Combined, we believe this work will expand our understanding of those biological systems influenced by adiponectin and may suggest more specifically, how adiponectin participates in the regulation of plasma osmolarity or other neuroendocrine functions in normal as well as disease situations such as diabetes.